Atrial fibrillation (hereinafter referred to as “AF”) is the most frequently observed type of arrhythmia in clinical examinations. Although not a lethal arrhythmia, AF causes cardiogenic cerebral embolism, and is therefore recognized as an arrhythmia that greatly affects vital prognoses and QOL. It is known that the onset of AF increases with age, and that repeated AF strokes lead to chronic (serious) AF (Non-patent Literature 1 and 2).
To prevent chronic AF, which causes difficulty in restoring sinus rhythm and increases the risk of cardiogenic cerebral embolism, early defibrillation and subsequent prevention of recurrence (maintenance of the sinus rhythm) are required. Antiarrhythmic drugs (classes I and III) are most commonly used as pharmacotherapy, but these drugs achieve insufficient therapeutic effects, while causing serious side effects such as a proarrhythmic effect (Non-patent Literature 3).
The onset of AF is triggered by atrial premature contraction with underlying causes such as intra-atrial conduction delay, and shortening and heterogeneity of the atrial refractory period (Non-patent Literature 4). It is known that the prolongation of refractory period of atrial muscle can terminate AF (defibrillation), or prevent the occurrence of AF. The action potential duration of the mammalian cardiac muscle is predominantly determined by voltage-dependent K+ channels. It is known that inhibition of the K+ channel prolongs myocardial action potential duration, which results in prolongation of the refractory period (Non-patent Literature 5). The action mechanism of class III antiarrhythmic drugs (e.g., Dofetilide) is to inhibit K+ current (IKr) encoded by HERG. However, since IKr is present in both the atria and ventricles, such drugs might cause ventricular arrhythmias such as torsades de pointes (Non-patent Literature 6).
K+ current (Ikur), encoded by Kv1.5, has been identified as a K+ channel that is specifically expressed only in human atria (Non-patent Literature 7, 8 and 9). Muscarine potassium current (IKAch), encoded by the two genes known as GIRK1 and GIRK4, is known as a K+ channel specifically expressed in human atria (Non-patent Literature 10). Accordingly, a pharmacologically acceptable substance that selectively blocks the IKur current (Kv1.5 channel) or the IKAch current (GIRK1/4 channel) can act selectively on the atrial muscle, and is considered effective to exclude the proarrhythmic effect caused by prolonged action potential duration of the ventricular muscle.
The present inventors conducted research to find a compound that can selectively block the Kv1.5 channel or the GIRK1/4 channel. As a result, they found that a novel benzo[b][1,4]diazepine-2,4-dione compound can be used as such a desired compound, and filed a patent application on the compound (Patent Literature 1). Note that Patent Literature 1 was not published on the filing date (Aug. 21, 2009) of the U.S. provisional application No. 61/235,988, which is the priority application of the present international application.